The present invention relates to a pharmaceutical preparation controlled to release a medicinal active ingredient at a targeted site the gastrointestinal tract, and more particularly to a pharmaceutical preparation for oral administration from which a medicinal active ingredient can be selectively delivered to any specific site in the intestinal tract.
Selective delivery of a medicinal active ingredient to a specific site in the intestinal tract has been desired in drug therapies, for instance, a local therapy for inflammatory disease in the intestinal tract such as ulcerative colitis or Crohn's disease, or an oral administrative therapy with a medicinal compound of a peptide which is apt to be decomposed chemically or enzymatically in the intestinal tract, with a medicinal compound of which the absorption site is limited, or with other medicinal compound.
In order to efficiently realize the selective delivery of a medicinal active ingredient to a specific site in the intestinal tract, it is necessary to design a pharmaceutical preparation taking into account the physical and physiological environment in the human gastrointestinal tract and the traveling time of the pharmaceutical preparation in the intestinal tract. With respect to the physical and physiological environment in the gastrointestinal tract, it is recognized that the value of pH in the stomach is usually 1.8 to 4.5 in a healthy human and that the value of pH in the intestines is 6.5 to 7.5 and the pH does not essentially differ between the small intestine and the large intestine. According to the results of the widespread research of Davis et al., the residence time of a pharmaceutical preparation in the human stomach is 0.5 to 10 hours and further not only the inter-individual variation thereof is large, but also the residence time is considerably influenced, for example, by feeding, a size of the pharmaceutical preparation to be administered and the like. However, the traveling time of a pharmaceutical preparation through the small intestine is generally recognized to be 3.+-.1 hours and the inter- and intra-individual variation is relatively small (Journal of Controlled Release, 2, 27-38 (1985)).
With respect to a method by which a medicinal active ingredient can be selectively delivered to a specific site in the intestinal tract, hitherto various researches have been done. There have been proposed a pharmaceutical preparation wherein a sustained release pharmaceutical preparation is coated with an enteric coating (Annals of the New York Academy of Science, 618, 428-440 (1991)), a pharmaceutical preparation obtained by utilizing a technique for controlling the starting time of the release (Chemical & Pharmaceutical Bulletin. 3036-3041 (1992)) and the like, as well as pharmaceutical preparations obtained by using known techniques such as an enteric pharmaceutical preparation and a sustained release pharmaceutical preparation.
However, every conventional method has a problem such as insufficient site-selectivity or poor practicality due to peculiarity of the material to be used. For example, in case of using the enteric pharmaceutical preparation, the release of a medicinal active ingredient starts abruptly at the upper small intestine resulting in consumption of almost of the medicinal active ingredient by absorption or decomposition before the medicinal active ingredient reaches the targeted site in the intestine, although the release of the medicinal active ingredient can be effectively suppressed in the stomach. In case using the sustained release pharmaceutical preparation, a considerable amount of a medicinal active ingredient is released when the pharmaceutical preparation stays in the stomach and passes through the small intestine because the medicinal active ingredient is continuously released.
Further, in order to release a medicinal active ingredient at the large intestine, there has been recently developed a system utilizing the ecosystem of specific microorganisms in the large intestine. For example, in a pharmaceutical preparation wherein a composition containing a medicinal active ingredient is coated with a novel polymer having an azo group, or the composition containing a medicinal active ingredient is dispersed in the new polymer having an azo group to form a matrix type of pharmaceutical preparation (Science, 233, 1081-1084 (1986)), the polymer is decomposed in the large intestine by enterobacteria having azo-reductase activity and the medicinal active ingredient is thereby released at the large intestine. However, for practical use, there are still many problems to be solved, for example, regarding the safety of the polymer itself, the controllability of the decomposition rate thereof, and the like.
An object of the present invention is to solve the above-mentioned problems the conventional pharmaceutical preparations, and provide a pharmaceutical preparation for oral administration by which a medicinal active ingredient can be effectively released at a targeted site in the intestinal tract.
This and the other objects of the present invention will become apparent from the description hereinafter.